Someone once said “all good things come with research.” Wait, they didn’t?!, oh well, that must be because research can be tedious and time consuming. I personally love researching all of that technical boring jargon that might have already put you to sleep for the night (I mean, what else should I do with my time?), and I have done some of it for you here.
All drugs, vaccines, etc start with a research and development phase. In the case of pharmaceuticals drugs can have what is termed an off-target effect. These sort of discoveries have been popping up in the news by the dozen with headlines that read, “cancer drug has new off-target effect and found to treat ___________.” Other discoveries can include new technologies (in this world there is about one or two of these per week it seems like). Computing softwares allow scientists to analyze hundreds or even thousands or more of potential therapeutic compounds. I know that is impressive and you are probably thinking with technology like this, everything should be cured, right?! (heavy breathing). Well, no, once these potential candidates are found, they have to be tested. Now, let’s reign in that excitement these candidates are no closer to being ingested by a human than they were five minutes ago (FDA, 2018).
What’s Next Then…?
Experiments have to be designed and completed to collect basic data (no, not like the kind that leads to the reason why you see ads for certain products, practically as soon as you think about them). Scientists might begin to collect information using an ADME assay. What this does is test the compounds absorption, distribution, metabolism, and excretion. It is important to find out how a compound works and whether or not it improves something. During the development stage, questions such as proper dosing, how the drug will be administered, and the potential toxicities are all explored. This is not an exhaustive list but it should provide you with enough information to move forward (FDA, 2018). Sounds quick and simple right? Well, no actually according to a brochure published by Northwestern University (2015), it can take up to 3 to 5 years to complete this stage. This is not including any catastrophic set backs, like a global pandemic. If we take a look at the average range of compounds sent through this screening process, on average it is between 5,000 and 10,000 compounds (Northwestern University, 2015).
All About that Pre-Clinical
Wait, wait, slow your roll. We still can’t just put this molecule in a capsule and give it to someone yet. The studies in this stage are either performed in vitro or in vivo. If you do not know what these terms are, don’t worry, either do I (just kidding). An in vitro study is conducted in something like a petri dish or a test tube. So then what is an in vivo study then? It sounds pretty hip right? At this stage the in vivo studies involve a laboratory animal. Studies are planned are conducted using the guidelines established and outlined in the good laboratory practices regulations. Data is then collected on proper dosing and toxicity levels. This helps to minimize the poisoning of your participants. Let’s keep in mind that it is important to make sure that these candidates work as therapeutics and help people (more than we can say for other types of candidates, amirite?) Once all of this data has been appropriately analyzed the process of developing the clinical trials can begin. At this stage, we begin to see a shortening in the time it takes to get the compounds to the clinical stage. This stage can take between one and two years to complete (Matthews, Hanison, & Nirmalan, 2016). Remember those 5 to 10 thousand compounds we started with? No? Me either, and that is because we only have about 250 that make it to the pre-clinical stage. Image that for a minute? All those long hours of bench science to walk away with only about 250 compounds. (FDA, 2018; Matthews, Hanison, & Nirmalan, 2016; Northwestern University, 2015; Phrma, 2015).
Clinical Trials – the Judge and the Jury
You’re probably thinking to yourself, this is a blog on interpreting hard/medical science. How does this relate to law, well over the next six to seven years, five of those 250 out of 10,000 compounds make their way through phase 1, phase 2, and phase 3 clinical trials (Northwestern University, 2015; Phrma, 2015). Along the way, their effectiveness (efficacy) and safety are observed and ultimately “judged”. The “jury,” which is composed of the scientists and the company will access the results and that will help decide which one’s come to market.
Let’s talk phases, using the recent reopening from the lockdown as an example. Consider Phase 1, a small group of roughly 20 to 100 people that are in good health but also suffer from the desired disease or condition. These studies tend to last for several months and the important take aways are the data on safety and dosages. Roughly, 70 percent of all drugs move from phase 1 to phase 2. This is important to remember when you are doing your own research. Set realistic expectations when you are reading phase 1 clinical trial results or reading about them in the media. Ever wonder why you hear about a specific compound being the next miracle and then all of a sudden it falls off the face of the earth? Well, this is part of that answer (FDA, 2018).
Phase 2 – these trials are larger in scale and can include up to several hundred individuals that all have the targeted disease or condition. Phase 2 trials can last for as little as several months or as long as two years. Efficacy and side effects are examined during this stage. It is important to know how effective that drug is at treated the specific disease/disorder that it is intended to. Here is also where scientists begin to log all of the side effects these medications can have. If I tried to explain all of this in one blog post, you’d be reading and I would be writing my first textbook. And, to be very honest that isn’t why I started this. I am doing this to give you a basic over of this stuff all in one place and try and make it some of it entertaining. Now, approximately how many drugs do you think move into the next phase? A. 24%, B. 95%, C. 33%, D. None. Think about it for a minute before proceeding. I know, I know, you didn’t sign up for quizzes but I am hoping to help you sharpen your critical thinking skills. The answer to this question is C, only 33 percent of those compounds make it to the next stage. That is just under half of the compounds from phase 1, bye bye miracle cures. It can be disheartening to think that something that showed so much promise, falls flat in the end but maybe that isn’t the last chapter for these potential medicines (FDA, 2018).
Phase 3/4 – Trials of this size consist of 300 to about 3,000 volunteers, and you guessed it all having the desired disease/disorder. These studies tend to be much longer and can go on for 1 to 4 years. Phase 3 trials are used to discover and watch for adverse reactions, while still taking the time to collect data on the efficacy of the compound. Only 25 to 30% of these phase 2 compounds pass this phase and move into a massive phase 4 trial (these consist of thousands of participants) or is submitted to the FDA (FDA, 2018).
The FDA – The Executioner
Now, the headline of this paragraph aside, the FDA is all three. Companies submit a new drug application (NDA), which is a comprehensive narrative all about this drug. The case has to be made that this drug is both safe and has a good efficacy. All of the data from every stage is submitted. This process can take one to two years to gain approval, and not every one will (Hence, the executioner)(Northwestern University, 2015; Phrma, 2015). NDAs can be delay if they are deemed incomplete by the review team. Since these NDAs can be considerably long they are broken down into smaller sections and distributed among a group of reviewers. The FDA also sends inspectors to the sites of the clinical trials to make sure that everything is up to their standards. If FDA approval is granted, which essentially means that the drug was proven both safe and effective for the use it was developed for. The company will work along side the FDA to improve the labelling of the drug and make sure that the prescribing information is in essence, “on point” (FDA, 2018).
AAAATTTTT LAAAAASSSTTTT, Myyyy Drug has Come Along.
In short, the FDA monitors the drugs for safety and efficacy continuously after they are brought to market. For the purposes of this review on clinical trials, we will not get heavily intrenched in patents or generic drugs for this post. You are already probably thinking to yourself this an un-blogging believable amount of information to take in. Hopefully, after you have read this post you can look at and evaluate the validity of news articles, clinical trials, and Uncle JimBo’s words of wisdom (We still don’t know why mom invites him to these things). You know we all have one, whether we like to admit it or not.
The Great Budget Blowout
Another very important fundamental that needs to be considered is funding, thats right, I will stress this again FUNDING!!! Why am I yelling this word at you through this screen, well, it could be because I feel like there is something that is stopping you from hearing me (Might be the distance). No, this is something that can stop promising compounds, vaccines, your new Lamborghini dead in their tracks. Despite containing the word fun, there is nothing fun about not having enough of it. An example of what can happen when you receive the proper amount of funding is what happened with the COVID-19 vaccines. Having access to the necessary capital can speed along the time IN-BETWEEN these trials. I am going to stress another point here, IN-BETWEEN, having all of this money does not shorten the amount of time these trials last. It only allows the companies to head straight from one trial to the next or to buy all of the key reagents needed. This is just one of the many factors that helped to speed up the process that got these amazing vaccines to market. A 2020 study conducted by Wouters, McKee, and Luyten and published in the JAMA estimates that the total cost of drug development for a single drug/compound can range from $314 million to $2.8 billion dollars. The data from this study was compiled from drugs that had been approved by the FDA. The average cost that the researchers calculated was roughly $985 million dollars (Wouters, McKee, & Luyten, 2020). This is more money than mostly all of us will see in our entire lives (unless this blog takes off, heres to hoping). Now, imagine this for a second this study had a sample size of 63 out of the 355 drugs/biological agents that were approved between 2009 and 2018 (Wouters, McKee, & Luyten, 2020). This number doesn’t include any of the drugs that have failed to pass the FDA approval process. Using the average (which we will round up to 1 billion) for this example, in nine years it took roughly $355 billion dollars to get us 355 new therapeutics (Approximately 40 drugs per year). When we think about the total cost for just one of these therapeutics, we can see why out of 10,000 or so compounds only five make it to the clinical trials.
References
FDA, (2018), The drug development process. Retrieved from https://www.fda.gov/patients/learn-about-drug-and-device-approvals/drug-development-process on 02/21/2021
Matthews, H., & Nirmalan, N., (2016). “Omics”-Informed drug and biomarker discovery: Opportunities, challenges, and future perspectives. Proteomes, 4(28), doi:10.3390/proteomes4030028
Northwestern University, (2015). Drug discovery and development, understanding the R&D process. Northwestern University, cited in Matthews & Nirmalan, 2016.
Phrma, (2015). Biopharmaceutical research and development, the process behind new medicines. Phrma.org cited in Matthews & Nirmalan, 2016.
Wouters, O., McKee, M., & Luyten, J., (2020). Estimated research and development investment needed to bring a new medicine to market, 2009-2018. JAMA, 323(9):844-853, doi:10.1001/jama.2020.1166
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